SUMMARY/ABSTRACT Pulmonary hypertension due to left heart failure (PH-LHF) is associated with high mortality. Current thinking is that PH-LHF begins as a passive process due to elevated left atrial filling pressures that increase pressures in the pulmonary veins. This early stage is termed isolated post-capillary PH (Ipc-PH) and is diagnosed by elevated mean pulmonary artery pressure with normal pulmonary vascular resistance (PVR). Combined post- and pre-capillary PH (Cpc-PH) is diagnosed when PVR is increased in this setting and confers an additional increase in mortality. Mechanisms underlying disease development and progression are poorly understood. Our overarching goal in this proposal is to discover the mechanical and biological mechanisms that drive transition from Ipc-PH to Cpc-PH and the development of (RV) right ventricular failure. Aim 1: To investigate the biomechanical and mechanobiological progression of Ipc-PH to Cpc-PH and RVF. In an established mouse model, we will quantify pulmonary vascular and RV biomechanics during disease progression as well as expression of mediators altered by shear stress and stretch. In two swine models, using a unique and comprehensive suite of invasive and noninvasive assays, we will quantify flow and pressure waveforms, and pulmonary vascular and RV biomechanics and mechanobiology, including RV-pulmonary vascular interactions and expression of mechanotransducers ET-1, eNOS, PECAM-1, and Twist1. Aim 2: To determine the roles of mechanical stimuli and mechanotransduction in disease progression. Using an existing computational model of the pulmonary circulation and a novel capillary sheet flow model, we will predict the impact of LHF-induced changes in pulmonary vascular pressures, flow, and biomechanics on shear stress and stretch in each compartment of the pulmonary vasculature, including the capillaries. Then, using well-established systems for imposing shear stress and stretch on cells in vitro, we will test the hypothesis that these mechanical stimuli drive key aspects of remodeling in human pulmonary endothelial cells. Finally, to investigate the balance between adaptive and maladaptive remodeling driven by ET-1 mechanotransduction, we will study disease progression in mice with endothelial cell specific knockout of ET-1.